This application relates to liquid pharmaceutical compositions for the intranasal administration of apomorphine.
Apomorphine (6aβ-aporphine-10,11-diol) (structure below) is a potent dopamine D1- and D2-receptor agonist used primarily in the management of Parkinson's Disease. The use of apomorphine for managing erectile dysfunction has also been reported. Oral bioavailability of apomorphine is low and for the treatment of Parkinson's disease the drug is administered by subcutaneous injection and may have to be given several times daily, typically at a dose in the range of from 1 to 10 mg of the hydrochloride salt, which is in the form of a hemihydrate. Multiple daily injections can be inconvenient to the patient and this can lead to compliance problems and alternative routes of administration may have advantages.
Chemical structure of apomorphine hydrochloride hemihydrate:

Formulations for intranasal administration of apomorphine have been reported elsewhere. For example, WO 99/27905 describes powder and solution formulations containing polymers designed to modify apomorphine absorption characteristics. Solution compositions for treating erectile dysfunction are described in U.S. Pat. No. 6,740,660. Powder compositions for treating Parkinson's disease are described in U.S. Pat. No. 5,756,483. Ugwoke et al (Eur J Pharm Sci., 9, 213-9, 1999) describe mucoadhesive apomorphine powder formulations containing Carbopol 971P and polycarbophil.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Apomorphine is most commonly used in the hydrochloride salt form, which typically exists as a hemihydrate. As used herein the term “apomorphine” refers to the drug in non-salt or salt forms and in all states of hydration. Any reference to the amount of apomorphine in this document refers to the amount of apomorphine hydrochloride hemihydrate. Other salt forms of apomorphine which could be used in the present invention include, but are not limited to, mesilate, citrate, nitrate, lactate, maleate, tartrate, phosphate, succinate, fumarate and gluconate salts.
The saturated aqueous solubility of apomorphine hydrochloride is around 20 mg/ml at room temperature. In practice, it is not appropriate to prepare drug formulations in which the drug is present in an amount at or close to the saturated solubility of the drug. This is because there is a risk that the drug will precipitate out of solution unless the storage and usage conditions are very carefully controlled. Any precipitation or other change in the composition of the drug formulation would result in unreliable and/or variable amounts of drug being administered to patients on administration of a particular dosage volume. This has limited the use of the intranasal route for the delivery of apomorphine, particularly for the treatment/management of Parkinson's disease.
For intranasal delivery of a liquid formulation the maximum volume of liquid administered into each nostril should ideally not exceed 0.2 ml and be preferably 0.1 ml or less. Hence, using both nostrils and a solution containing 20 mg/ml apomorphine, the maximum achievable intranasal dose would be 8 mg.
Other problems associated with providing aqueous solutions of apomorphine include stability problems, particularly because apomorphine is highly susceptible to oxidation.